Monday, June 29, 2009

Most articles about CLL begin with the sentence, “CLL is the commonest type of leukaemia in the Western world.” However, the apparent incidence of CLL has fluctuated widely over the years. In Hansen’s magnum opus [1] published in 1973 and based on 189 cases of CLL followed for a long time, he reports on previous studies that found an incidence of 5.5 per 100,000 in 1949, 6.6 per 100,000 over the period 1943-52, and 6.4 per 100,000 between 1958 and 1961. In 1964 a Danish study found an incidence of 7.8 per 100,000.

This was in the days before immunophenotyping when any lymphocytosis over 10,000 per microlitre of relatively appropriate morphology was designated CLL. In a retrospective examination of patients previously diagnosed in our own unit we have identified patients misdiagnosed as CLL who in fact had splenic marginal zone lymphoma, mantle cell lymphoma, follicular lymphoma, small cell Sezary syndrome and T-cell prolymphocytic leukaemia. In our work as a reference center we have recognised that these types of mistakes were not rare. Immunophenotyping has excluded the majority of interlopers and as a result the perceived incidence of CLL fell between the nineteen seventies and nineteen nineties. Sgambati et al [2] reporting on statistics from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) Program described a fall in incidence rates for CLL for white males from 4.2 per 100,000 to 3.2 per 100,000 between 1973 and 1976 while the rate for white females fell from 3.8 to 2.6 over the same period. The rates for those of African-American, Hispanic or Asian origin were much lower.

Exactly how many cases of CLL are collected depends on how assiduous is the collection. Simply relying on death certificates or hospital admissions will miss all those early stage patients that never progress and never require treatment. Between 1984 and 1988 Cartwright et al [3] enlisted the help of hematologists performing blood tests for one third of the population of England and Wales to register every new diagnosis of CLL. The annual incidence was 5.54 per 100,000 with a male to female ratio of 1.95. There was no temporal variation, but a threefold difference between districts. Racial differences could not explain the discrepancies, though districts where the disease was commoner tended to have more old people. What was noticeable was that the disease was apparently commoner where the hematologists took a special interest in the disease, suggesting that such specialists would be more likely to make the diagnosis with a relatively low lymphocyte count that less obsessed doctors might pass as normal.

Guidelines for the diagnosis of CLL were published in 1988 by a National Cancer Institute Working Group (NCI-WG) [4] and in 1989 by the International Workshop on CLL (IWCLL) [5]. The former required a lymphocytosis of >5 x 109/L but the latter a lymphocytosis of >10 x 109/L. This confusion was removed by the 1996 guidelines published by the NCI-WG [6] which settled on a lymphocytosis of >5 x 109/L but has been further complicated by the 2008 guidelines published by the IWCLL [7] which raise the threshold to a B-cell lymphocytosis of >5 x 109/L. In 2002 Rawstron et al [8] discovered that 3.5% of the population over the age of 40 harbors a population of cells immunophenotypically similar to those of CLL. More sensitive techniques suggest that this percentage might be as high as 12% [9]. This new entity, monoclonal B-cell lymphocytosis (MBL), seems to precede most new cases of CLL [10], but clearly most cases never progress to become CLL. Since individuals with MBL may have up to 5 x 109/L B lymphocytes, the new threshold for CLL was absolutely essential to distinguish between them.

In this issue of Leukemia Research, Seftel et al [11] have analyzed the effect that diagnosis by immunophenotyping has had on the incidence of CLL according to the 1996 criteria. The SEER figures for the period 1993-2004 give a combined incidence of CLL and small lymphocytic lymphoma (SLL) of 5.13 per 100,000 [12]. SLL is essentially the same disease as CLL in which the lymphoid expansion is confined to lymph nodes and not present in the blood. It differs from MBL in having definite lymph node enlargement. For the period 1996-2005 the Public Health Agency of Canada, using data from provincial cancer registries reported an incidence of 5.9/100,000 [13]. Seftel et al assembled the data from the provincial cancer registry at CancerCare Manitoba and supplemented these with flow cytometry reports from the two tertiary referral centers in Winnipeg. In both cases the data covered the period from January 1st 1998 to December 31st 2003.

The results of their study demonstrated the fragility of data from cancer registries. Although they assembled 813 patients, 14.5% had to be excluded for administrative reasons, mainly because the diagnosis had been made before the study period. This is a common problem, because diagnosis by a haematologist is very likely to predate a patient being brought to the attention of a cancer registry. A further 9.7% were excluded because of a wrong diagnosis, most commonly marginal zone lymphoma. Despite these exclusions the apparent incidence of CLL has risen. Over the study period as flow cytometry was more regularly used, the annual incidence went from 6.73/100,000 in 1998 to 9.40/100,000 in 2003. It was this apparent increase in early stage CLL that prompted Hoffbrand and Hamblin in 2007 to warn that patients were having the label ‘leukemia’ attached to them when they might realistically expect and normal and healthy lifespan [14].

The new 2008 guidelines for the diagnosis of CLL will have the effect of reducing the incidence since a B-cell lymphocytosis of 5x109/L roughly equates to a lymphocytosis of 11x109/L [15]; back to where we were in 1973. The new guidelines has been criticised on the grounds that there would be unintended consequences of cost and access, and that there was no established clinical relevance of making the change [16]. Furthermore, follow-up monitoring of patients with MBL would be more expensive since it would now have to include flow cytometry [16]. However, these criticisms have been rebuffed by the IWCLL working group although they admit that more work needs to be done at the MBL/CLL interface [17].

The true incidence of CLL remains a mystery. We shall have to await studies using the 2008 diagnostic criteria.

Today I went for my pre-chemo appointment and got the result of my scan. The previous scan showed an area around the ileocecal valve that was the presumed primary that was 3.2 cm in diameter and some thickening of the mesentery. In the scan of 10 days ago (taken during the 6th infusion) this ileocecal area was 2.0 cm in diameter and there were no other abnormalities on the scan. If we think of the original lesion as a sphere, it would have had a volume of 12.8 cubic cms. The volume of the current lesion is 3.14 cubic cms. In other words we are talking of three quarters of the volume of the cancer gone after less than half the treatment. It holds out the possibility of curative surgery when the chemo is finished, though this is not to be relied on.

Friday, June 26, 2009

Why have a blood transfusion? Is it a] to raise your hemoglobin? b] to improve your color? c] to improve the oxygen carrying capacity of your blood?

The answer, of course, is c] but while it will do both a] and b] it won't do c] immediately. Oxygen is carried by hemoglobin and is released to the tissues where it is needed. It is helped to do this by a chemical called 2,3,DPG. In order to release oxygen, its place on the hemoglobin molecule must be taken by this chemical. 2,3,DPG is manufactured by all cells from the burning of glucose (the process is known as glycolysis and the biochemical pathway is known as the Emden-Myerhoff pathway. The particular trick of producing 2,3,DPG is known as the Rapaport-Leubering Shuttle). If a cell is not metabolising glucose then it won't make any 2,3,DPG, and this is what happens when blood is stored in a fridge. So when you receive blood from the blood bank it has very little 2,3,DPG and therefore the hemoglobin molecules cling on to their oxygen. That's why someone who has been transfused gets no immediate benefit from it; it can't release its oxygen to the tissues until it regenerates 2,3,DPG, which takes a couple of days.

This is one of the reasons that patients are dissatisfied with blood transfusion. That and the risk of transmitting viruses, or prions, or making their cancer worse by suppressing their immunity. In fact blood transfusion is very safe. Blood is screened for HIV, hepatitis B and C and a host of other possible infections. It cannot be screened for prions, but the risk of developing new variant CJD from transfusion is vanishingly small. The greatest risk of a transfusion is that some idiot will give you the wrong blood.

The alternative is EPO. Lots of cancer patients have been given it, but the unfortunate fact is that it shortens life. A recent meta-analysis published in the Lancet looked at 53 separate trials involving 13,933 patients. Although the effect was not great (a hazard ration of 1.06) it was statistically significant. Partly this effect is because EPO may raise the hemoglobin too much and the thrombotic complications of polycythemia come into play, but also there is the worrying fact that EPO is a growth factor for some tumors.

With so much to worry about we need to look at anemia again. In some cases the problem can be sorted with iron therapy. (Oral iron is best; there is no evidence that intravenous or intramuscular iron is more likely have a response or have a quicker response.) But we need to be able to recognise iron deficiency (which is almost always caused by bleeding). The easiest way is to look at the mean cell volume on the blood count. If this is below 80 fl then iron deficiency is the most likely diagnosis. Thalassemia trait can cause a low MCV and this is an important catch for people of Mediterranean background, but the only other cause of a low MCV is the anemia of chronic disorders (ACD).

I have bee surprised recently by how little even hematologists know about ACD. They seem to be unaware that it can cause a low MCV. I can only think that they have never looked at the blood counts of patients with rheumatoid arthritis, ulcerative colitis and Crohn's disease, let alone people with chronic infections or disseminated cancer. The serum iron in ACD can be as low as it is in iron deficiency, as can the MCV. The difference is that the iron binding capacity or the blood (or the serum transferrin) is raised in iron deficiency and lowered in ACD. Serum ferritin is low in iron deficiency and raised in ACD.

What happens in ACD is that the macrophages are over active and snaffle all the iron in the body and won't release it to the newly formed red blood cells. We now know that a chemical called hepcidin, a small peptide produced by the liver that inhibits both iron absorption and release of iron from the macrophages. Patients with excess hepcidin will not respond to more iron, whether oral or intravenous, nor to EPO. Only blood transfusion will raise the hemoglobin.

High hepcidin levels are found in association with high sed rates, high CRPs, high IL-6 levels and other indicators of inflammation.

Thursday, June 25, 2009

Thirty-five years ago at the beginning of my consultant career I wrote a ‘Personal View’ for the BMJ. At the time I was frustrated by the inappropriateness of the hurdles I had to scamper over to achieve that status, but full of hope for the future and anticipating the exciting developments that the application of science to medicine would bring. Now that I have retired and become a patient, how does the NHS look?

In many ways there has been a great improvement. The plant that I am being treated in is far superior to the make-do-and-mend Victorian buildings that I practised in at the start of my career. There are many more consultants; for much of my career I had three consultant physician and three consultant surgeon colleagues – now there are more than thirty of each at our District General Hospital (DGH). The imaging departments have been revolutionised, so much so that autopsies have become almost a thing of the past – nobody seems to die undiagnosed – and the exploratory laparotomy is as archaic as the tuberculosis sanatorium.

There has been an enormous increase in regulation, much of it necessary, I am sure. I can think of colleagues who ‘paddled their own canoes’ in the hospital environment, not really caring how it affected their colleagues, who were powerless to influence what they did. The introduction of managers who really managed made a difference. On the other hand many of the innovations that I was able to introduce and the advances that I effected would probably have been impossible under the current regime. They would have been judged inappropriate in a DGH. The time and energy involved in bringing research enterprises to the clinic is certainly excessive now.

Junior doctors are much more junior now and hardly seem to work for any hours. As a Senior Registrar I expected to know everything about every patient under my care, even down to the minutest detail about how long an infusion lasted, what side effects were suffered, and whether the neutrophils were granulated or not. It seems that today that degree of surveillance has been delegated to the nurses and laboratory scientists while the more junior registrars are away on diversity training or maternity leave.

Of course, nurses are not the nurses I knew when I started out. No more ‘mopping fevered brows’ but they really are excellent at running wards. They form a smooth cadre of carers with the Health Care Assistants, and my experience as an in-patient was that things got done on time according to well-designed protocols.

Ah protocols! When I ran a laboratory we had to introduce standard operating procedures (SOP) which ensured that every blood test was done in exactly the same way so that no random variation crept in. There was even an SOP for answering the telephone. (“Good morning, how may I help you?”) I can see that as you deskill the hospital it is necessary to introduce rigid protocols and deskilling has become necessary with shorter working hours, more training and the really bright people being seconded to very complicated tasks, but has that rigidity gone too far?

I give you three examples. In the first the rigid rule was ‘no more than four doses of paracetamol (acetaminophen) in 24 hours’. The patient in question had his post-operative pain well controlled by paracetamol 1 gram four hourly. When he awoke at four am and asked for more paracetamol he was denied because only 23 hours had passed. He could either wait for an hour or have a morphine injection. Now I know paracetamol can be lethal. The fatal dose is around 150 mg/kg. For an 80 kg man (for such he was) that makes the potential lethal dose 12 grams if given over an hour. Even in a man with alcohol problems (which he did not have) there is no way that 5 grams in 24 hours could be harmful. Besides, there is a very effective antidote. Because morphine made him sick (and he was not boarded for an anti-emetic) this patient elected to suffer in silence for an hour.

The second rigid rule was ‘no-one but a doctor is allowed to prescribe intravenous fluids’. In this case it was clearly the junior doctor’s duty to write up the intravenous fluids for the next 24 hours. But guess what, she was too busy. As a recent graduate she found getting through her day’s tasks onerous and she went off duty at 5pm (something that is compulsory these days unless you want a black mark). The ‘hospital at night’ team doesn’t really work unless funded at extravagant levels. Despite being rung on numerous occasions, the F2 (an NHS term for a resident doctor in his second year after qualifying) on duty never turned up on the ward to write up the fluids until 2am. The drip had stopped at midnight and no attempt had been made by the nursing staff to keep the drip open. Why should they? No further intravenous fluids had been prescribed. It took seven attempts from three different doctors and a nursing sister to resite the intravenous cannula. In the past the nurses would have accepted a telephoned instruction or even kept the same fluid regime running or at the very least kept the drip open with slowly running dextrose saline. Now they dare not.

The third rigid rule was ‘blood must not be transfused to patients who are pyrexial’. On this occasion the patient had had major hip surgery and dropped his haemoglobin from 140 g/L to 70 g/L. Blood was prescribed but before it could be given his temperature was noted to be 37.4 degrees C. Obviously blood could not be given! No matter that his pyrexia was almost certainly caused by the presence of several litres of altered blood in his thigh. Never mind someone had some ingenuity. They took the patient to an open window, divested him of his pyjama jacket and played an electric fan on him. When his temperature fell by the requisite 0.4 degrees C they transfused the blood and no, he didn’t catch pneumonia. As an aside, I recently came across a medico-legal case where in a similar situation a haemoglobin of 50 g/L was left untransfused because of a pyrexia. The poor woman became blind from her anaemia and it cost the hospital a lot of money in damages.

These three cases have this in common; in obeying the ‘rules’ nobody was available to think what the rules were there for. Such rules do not have the authority of the Law of the Medes and Persians; they are more like guidelines. They should be a spur to thinking and asking questions. But perhaps the NHS no longer employs thinkers.

Wednesday, June 24, 2009

Sorry to have been silent for so long. The chemotherapy wipes me out for a few days, but today I am on the mend. I have been gradually working through a number of articles in WORD and they will be posed over the next few days.

I understand that NICE have agreed that Revlimid should be paid for for the treatment of Myeloma, even though the cost per QALY is £43,000 (around $70,000). This is good news for CLL patients, though we wait to see how the economics will play out for CLL.

The myeloma people tell me that it has been quite difficult to recruit for the myeloma trials with the greatest difficulty coming from the West Midlands around Birmingham. So I was not surprised to hear a radio comment from Birmingham expressing dismay at the NICE decision. The speaker apparently believed that the money could be better spent of statins for everybody over 50 to prevent heart attacks and strokes. He is probably right in that the cost of statins is extremely low - around £7 ($11) a month. But he is wrong on several counts.

First, the NHS is basically a state funded insurance system. It exists on the premise that what you can't do for yourself the community will do for you. Few of us could find a quarter of a million for marrow transplant, but as a community, that transplant will cost us 0.4 pence each. We can afford a lot of those. In belonging to a society we agree to spend a few pennies each on a wide variety of enterprises - roads to travel on, schools to educate our children, an army and police force to protect us, and public health measures to prevent epidemics. Different societies differ by how much of this community support is provided privately and how much by the state, but in all societies individuals have to rely on the whole. I doubt that many would be happy about the military or the police force being provided by industrial companies, but in some lawless communities that may be the best option.

There is also a decision to be taken on thresholds. How much does the individual want to buy from the community for each of these services? Private refuse collection versus personal visits to landfill sites? Home schooling versus inner city schools? A Montana campsite and an AK47 versus New York's Finest? In the UK we have opted for more state provision of services than in the US, but less than in Sweden or Denmark. Where the threshold lies does not affect the principle of the social contract; it is there to insure the weakest against the highest costs. It therefore makes no sense for the NHS to pay $11 a month for a pill to protect citizens against heart attacks when if that is what they want to do they could easily afford to pay for it themselves. On the other hand treatment of myeloma with Revlimid is beyond the reach of most people unless the rest of the community join in.

There is a second reason why the NHS paying for statins is wrong, and it goes to the whole basis of insurance. When the NHS was first introduced it provided free hot water bottles. Now 1947 was a very cold winter and there was no central heating in the UK then. There might well be good public health reasons for providing everyone with a hot water bottle, but why should people not buy their own? In fact, even Nye Bevan saw the silliness of this and it was stopped.

When I insure my car or my house, I elect to accept an excess. This means that the first £100 or £200 of the claim I pay myself. Naturally, I don't make small claims. Although, I get benefit from paracetamol (acetaminophen) when I am receiving chemotherapy, I would not dream of asking for a free prescription for it. At less than a dime a day a think I can afford it. Those who volunteer to have an excess get lower premiums - there are not so many claims therefore they pay less.

The third reason that the NHS should not pay for statins is that strokes and heart attacks are largely self-inflicted wounds. What is the point of spending $11 a month when the customer is spending more than that on cigarettes and fatty foods to counteract their effect?

The final point I want to make is about personal freedom. People who have opted for cigarettes and whisky rather than statins have already taken a decision about their health. Bib Brother has no right to gainsay it. By all means educate people into making good restrictions; even prevent manufacturers from influencing people with biased propaganda (as cigarette advertising was banned), but when someone says they would rather enjoy a particular lifestyle than possibly prolong their time in an old people’s home, they must be listened to.

The nanny State can intrude too much. It starts by offering help and ends up being compulsory.

Friday, June 19, 2009

The dose reduction of oxaliplatin has left me less befuddled this time and perhaps the cold-induced parasthesiae are less. I have gone back to the steroids this time with heavy doses of lanzoprazole to avoid the indigestion. This means that I wake at 3am and start to compose a blog. This time I started thinking about titles.

In America President Clinton is still called President even though he is no longer the President. Senator is a prized title and I suppose there are many others. Every country has its own traditions. In Germany the wife of a University Professor who has a medical degree and a PhD is formally called "Frau Professor Doctor Doctor Schmidt". In America even a schoolteacher is known as Professor and most medical academics prefer to be called Doctor except in Europe where Professor is the more revered title.

Medical degrees is the UK are officially Bachelor of Medicine and Bachelor of Surgery (some Universities also add Master of Midwifery) yet everyone is called Doctor. In most other countries the qualifying degree is MD, though in some countries it is simply a license to practise. In the UK many people with a PhD do not call themselves Doctor for fear of being asked to officiate at an emergency. I notice that theologians like to call themselves the Reverend Doctor but musicians prefer Maestro to Dr. In the UK physicians look more to post-graduate diplomas to define their status. Thus MRCP or FRCS are more coveted than than MD or MB,BS. There used to be a qualifying degree called Licentiate of the College of Physicians and Membership of the College of Surgeons (LRCP, MRCS) which those who couldn't pass their University finals took, and for the really hopeless there was the Licentiate of the Society of Apothecaries of Cork which was parodied in the movie 'Doctor at Large' where dear old Cyril Cusack examines Donald Sinden in a ride on a pony and trap and the most difficult question is "What can you tell me about urea?" and Sinden's reply is "Do you mean the thing you hear with of the chemical substance?".

It used to be that when you passed the Diploma exams (which are rather like the Boards exams in the US) you were a Member for a few years and then were automatically promoted to a Fellow when they increased your annual subscription. That's why I have FRCP and FRCPath after my name. To become a hematologist in the UK you have to be doubly qualified in Pathology and Internal Medicine. Oxford and Southampton degrees are a bit different to everybody else's. Instead of having MDs and PhDs they have DMs and DPhils. Which is why my letters are DM (though I often write MD to avoid confusion). In the UK the MD is a research degree like a PhD (though it is usually on a clinical subject rather than a laboratory one. It can be awarded for a period of study in a time out from training or as a result of published works on a particular subject as mine was - 13 years of studying CLL.

Of course all these letters after someone's name can be very confusing. I remember being with Reg Clift in a line for refreshments at a meeting. Together with Don Thomas he pioneered the development of bone marrow transplantation in Seattle. Someone came up to Reg and asked what the letters FIMLS after his name meant. Reg wasn't a doctor (though he practised like one). Before Reg could answer, the then Editor of the Lancet who was an Immunologist piped up, "It stands for Fellow of the Institute of Medical-Laboratory Scientists. I've got twenty of those working for me back in England." To which Reg responded, "That's a coincidence, I've got 20 MDs working for me."

Not all letters after the name are what they seem. FRSM simply means that you belong to an expensive Gentleman's Club in central London. It does have a superb Library and a wonderful restaurant as well as cheap lodging so it is worth the annual subscription, but FRSH is a simply a vanity purchase to fool the customers. Buying letters after your name is a common practise; Oxford and Cambridge BAs can upgrade their degrees to MAs after a year for only 10 quid. In the past the only MD degrees awarded were to Oxford and Cambridge graduates who had to take examinations in Latin, Greek and Physic. Edward Jenner, one of the greatest physicians ever, (he invented smallpox vaccination) trained as an apprentice surgeon and qualified as an Apothecary. He couldn't get an MD because he had no Latin or Greek, for the same reason he could not become a member of the Royal College of Physicians. Eventually he bought an MD from Glasgow University for £100; even then the Scots were canny with money. It should be remembered that at the time Jenner was already a Fellow of the Royal Society (the highest Scientific Accolade), not for smallpox, but for discovering how the fledgling cuckoo removed the other eggs and birds from the nest.

Not many medics make FRS and to compensate for that a few years ago a few senior academic doctors set up a new Society, the Academy of Medical Scientists. Leading medical academics were invited to become FMedSci. They guard their doors assiduously against anyone who has not achieved very much yet.

Nowadays it seems that everyone wants to be called Doctor; Dentists, back manipulators, acupuncturists, and even podiatrists. In Russia doctors are called "vrach" I believe, which being translated means "leech". Surgeons in the UK are offended by being called Doctor. Once they have their FRCS they insist on being called Mister. This dates from their origin as barber-surgeons (like Sweeney Todd).

In the church there are many titles, as I illustrated in a previous blog. But it is Bishops I want to attack. The Greek word 'episcopos' which is translated 'bishop' literally means overseer and it is used interchangeably in the New Testament with 'presbutos' which is often translated as 'priest' but actually means 'elder'. The NT only recognises two clerical offices in the church: elder and deacon (which could also be translated as 'minister' or 'servant'. The problem arose when bishops got too big for their mitres ans started assuming and authoritative power. The Bible assumes a plurality of elders in a local church, all of whom should be apt to teach (a quality missing from the list of requirements for deacons). Some elders (but not all) are to be set aside for the preaching of the word and the elders as a whole are to be given the governance of the church, but the NT specifically warns against getting involved in the affairs of the world. It is therefore a nonsense that certain Bishops are guaranteed seats in the British House of Lords, that hangover from feudal times.

Permit this small digression. I watched the Trooping of the Color last week on the Queen's birthday. It was a colorful pageant with clever marching and martial music. I would not want to see it lost, but all the various ranks: knights, baronets, marquises, viscounts, barons, earls and dukes seem to be an affectation too far. The House of Lords as a chamber for refining and modifying legislation seems a sensible organisation, though it is largely a resting place for retired politicians, many of whom remain the crooks they were in the House of Commons.

Anyway, back to Bishops. They quickly became secular authorities in the Roman Catholic Church. Bishop Odo fought with William the Conqueror. Others in England became Lord Chancellors of effectively Prime Ministers. Even in the Church Bishops sought to lord it over people, specifically against the instructions given in the New Testament.

The Quakers have it right, I think. Everyone there is plain John Smith or Jane Baker. If a qualifier is needed it could be Jane Baker, secretary, or John Smith, businessman. I would be happy to be Terry Hamblin, with the physician only added if someone needed one.

Wednesday, June 17, 2009

I had my sixth course today with a 25% dose reduction of the oxaliplatin. I already have the cold induced pins and needles, but let's wait and see if the dose reduction does reduce the side effects. Tomorrow I have a CT scan to assess response.

What have I been doing recently? Mostly reading. The books that I have completed in the past couple of weeks since finishing the new Lee Child are three thrillers: "Drop Shot" by Harlen Coben - with much borrowing from Hitchcock's "Strangers on a Train" - "A Good Day to Die" by Simon Kernick and "The Last Watchman" by Robert Crais. I have also read Bernard Cornwell's "Sharpe's Story" a make weight done for charity and I have re-read CS Lewis's "Out of the Silent Planet". I last read that about 50 years ago and could remember very little of it. I read it in conjunction with "Planet Narnia" which I am working my way through. The first of the Science fiction trilogy is about Mars which looms large in the Lewis pantheon. "Prince Caspian" in my next book and also comes under the Martian influence. "War of the Worlds" by HG Wells expressly states the link between Mars and war and Lewis is an interesting Christian writer who clearly feels that pacifism is wrong. He famously wrote a piece entitled, "Why I am not a pacifist".

If I felt fitter I would write at length about this subject, but I will finish with a quote from the Cornwell book and invite my readers to comment on the question of Christianity and pacifism. "A soldier fights battles for those who cannot fight for themselves."

Sunday, June 14, 2009

After this morning's sermon by Bev Savage I felt well enough and compelled to write this sonnet.

But Jesus was not Jesus then, no moreThe Virgin Mary’s son; He was the Word,With God, the Three in One, in rapt rapportHeld fast by love. The Holy Three conferredAnd made the sky, the earth, the sea; His handIn each creative act. The Spirit soaredAbove the seas before that great command,“Let there be light!” He was the Light; adoredBy angels. Darkness could not comprehend.Then there was life, of countless, teeming kind.In Him was life and His that life to lend;The light of men; for Man he had designedTo hold His image and while thus constrainedTo free from bondage those whom sin had stained.

Thanks to those who have been praying. I definitely feel better today. My appetite has returned and for the first time in a month we were able to go out for a walk. If you had any doubt that I was under spiritual attack, doubt no more. I have even begun writing a poem based on Bev Savage's sermon this morning.

Friday, June 12, 2009

I'm not sure whether I have told this story before, but when I was in charge of blood transfusion transfusion at my old hospital (which lasted for 29 years), there were just two occasions when we managed to give a patient the wrong blood. On both occasions we gave a Group O patient Group A blood. The first time was in August. The orthopedic ward was closing for the summer, so patients having hip surgery returned from the operating theater to the general surgery ward for recovery. Two patients returned at the same time, and the ward sister instructed a nurse to set up a unit of blood on Mr A. The nurse confused Mr A with Mr B, failed to carry out the usual check, did not involve another nurse as she should and gave Mr A's blood to Mr B. Mr B had a severe transfusion reaction, went into kidney failure, but, fortunately, made a complete recovery.

On the second occasion, five years later, the mistake was made by a laboratory technician cross matching the blood at night. Here, he picked up a tube of blood to cross match and found some compatible blood. It was only after he had issued the blood to the ward that he realized that the tube of blood he had matched against had not come from Mr X, but from Mr Y. Realizing his mistake he rushed over to the ward and snatched the drip out of the patient's arm. Only 20 mls had been transfused and the patient suffered no ill effects. The astonishing thing was that Mr B and Mr X were the same person. The only patient we had ever inflicted the wrong blood on in nearly 30 years and we did it to him twice!

Murphy's Law states that if anything can go wrong it will go wrong. When I first wrote about this remarkable coincidence, I coined the term 'Job's variant' of Murphy's Law; not only would everything go wrong that could go wrong, it would all go wrong at the very same time. If you read the book of Job, you will realize what I mean.

As I look back at the past 5 years I consider myself a victim of Job's variant. Many of my readers won't understand this, but those who know me best will realize that the cancer and its problems have just be the culmination of bad things happening to this family. If you understand what was at the back of Job's calamities you might begin to wonder if the same thing is not at the back of mine.

CS Lewis in the 'Screwtape Letters' tells us that the Devil welcomes both the materialist and the magician. He tells us that the two mistakes mankind makes about the Devil are to take an inordinate interest in him and to believe that he doesn't exist.

In "Tramp for the Lord", by Corrie Ten Boom she tells of a visit to Poland while it was still behind the Iron Curtain. Despite sleeping for a full eight hours she always awoke exhausted and weak. It wasn't that she had picked up an infection or was being poisoned by pollution. A local Pastor explained their predicament, "Your tiredness is nothing less than an attack of the devil. He does not like your work here in Poland, for the Antichrist is busy here, arranging his army." He then prayed over them, rebuking Satan. Thereafter the tiredness left them. Corrie Ten Boom further testified that they had felt the same tiredness on other speaking tours, even in some American cities, but on rebuking the devil in Jesus's name, the tiredness always left them.

How should we view this testimony? For those who do not know her, Corrie Ten Boom was a Dutch lady who was famous for hiding Jews from the Nazis in World War II. She was herself arrested and sent to the Ravensbruk concentration camp where her sister died. After the war she toured the world preaching a gospel of love and forgiveness, even on one occasion being confronted by one of her camp guards and being challenged to forgive him. She was not a fatuous, air-head Christian, but one who had really suffered for her faith. But she came from an old school Christianity (she was 50 when the war began); was her experience merely psychological?

The Bible tells us that our struggle is not against flesh and blood, but against the rulers, against the authorities, against the powers of this dark world and against the spiritual forces of evil in the heavenly realms. (Ephesians 6:12)

Why should I be attacked? The only prominent thing I can do now is witness through this blog. Many have told me how it has strengthened their faith. Satan, I am not going to stop writing this blog no matter what you throw against me. Reader, praying friend, if you want to know what to pray for, please pray against the evil one.

In the Book of Revelation we read of how Satan was brought down. "They overcame him by the blood of the Lamb and by the word of their testimony; they did not love their lives so much as to shrink from death." (Ch 12:11)

Thursday, June 11, 2009

Today has been a better day. I have felt well enough to cut the smaller of our lawns. I managed to get the date of my CT scan wrong. It is next Thursday, not today. My blood count was normal today - no sign of the heparin lowering my platelets.

Wednesday, June 10, 2009

I have been gradually improving since the weekend and I have put some work in on the chapter that is due next month.

DiagnosisThe diagnosis of CLL is superficially very easy. For most patients the only abnormality is in the blood count, which shows a lymphocytosis comprising small round cells consisting of mainly nucleus with very little cytoplasm. The nuclear chromatin is coarsely condensed and nucleoli are not usually visible. Cytoplasm appears as a pale blue rim in Romanowsky stained blood films. Characteristically there are cells present on the blood film that appear to have burst or disintegrated; these are known as ‘smudge’, ‘smear’ or ‘basket’ cells. An admixture of larger cells is usually seen. Typically, prolymphocytes are present with larger nuclei with less condensed chromatin and a single prominent nucleolus. The nucleus is often eccentric set in rather more abundant pale cytoplasm.

Very rarely cells with a nuclear cleft are seen leading to confusion with follicular lymphoma. The term ‘atypical CLL’ has been applied to cases of CLL where the number of prolymphocytes exceeds 10% or where the total of atypical cells including prolymphocytes, clefted cells and plasmacytoid cells exceeds 15%. Although it is a commonly used term it has no basis as a different disease entity and the term is just as often used to describe cases of CLL with atypical cell markers. Atypical cell morphology is often associated with the presence of certain chromosomal abnormalities, particularly trisomy 12.

The definitive diagnosis of CLL relies not on the cellular morphology, but on the immunophenotype. The cells are monoclonal. Clonality is assumed by the finding of a single immunoglobulin light chain type (either kappa or lambda) on the surface of the CLL cells, but the quantity of surface immunoglobulin is only about 10% of that on normal B cells. The cells are typically positive for CD5, CD19 and CD23 and negative for FMC7 and surface CD22. The immunoglobulin associated molecule CD79b is only weakly positive. The Matutes score utilizes these markers to differentiate CLL from other lymphoid tumors. In its latest guise it allocates one point each for positive staining for CD5 and CD23, one point for negative staining with FMC7 and one point each for weak or negative staining for surface Ig and either CD79b or CD22. Most cases of CLL have scores or 4 or 5; those scoring 3 often have ‘atypical’ CLL and those scoring 0-2 have other lymphoid tumors.

The monoclonal antibody FMC7 detects and epitope of CD20 which is obscured by changes in membrane cholesterol metabolism. CD20 is also only relatively weakly expressed on CLL cells compared to other B cells. There are other antigens that are differentially expressed on CLL cells, including CD43, CD11c, CD25, and very low levels of CD45, but these markers are of less value in distinguishing CLL from other B cells malignancies than those used in the Matutes score. Flow cytometric examination of CLL cells usually includes CD20 and CD52 in the examining panel since antibodies to these antigens are part of the therapeutic armory.

Clinical featuresApart from the lymphocytosis, patients may have accumulations of lymphocytes elsewhere. Peripheral lymphadenopathy in cervical, axillary and inguinal regions must be looked for since lymph node enlargement in these areas form the basis of the clinical staging systems as do enlargement of the spleen and liver. More comprehensive lymphadenopathy may be detected by imaging techniques such as abdominal ultrasound (US) and computerized tomography (CT), but these techniques play no part in clinical staging. It should be emphasized that there is usually no place for CT scanning in the initial examination of most patients with CLL and staging based on CT findings can lead to serious mistreatment of patients.

The other area of lymphocytic infiltration that is clinically important is the bone marrow. This is assessed by measurement of the haemoglobin and platelet count and there is usually no need for bone marrow examination in the initial assessment of patients with CLL. Of course, there are other reasons than bone marrow infiltration for anemia and thrombocytopenia in CLL, such as autoimmunity, iron deficiency and hypersplenism. It is important to exclude these when clinical staging is assessed.

Two forms of clinical staging are currently used; Rai staging in America and Binet staging in Europe. Details of these systems are given in Table 1. Although they differ in detail they both in effect measure tumor mass, and neither measures the pace of disease. Both have prognostic value and both suffer from the same defects (such as using the same threshold haemoglobin value for males and females). Both have stood the test of time and both remain valuable despite the appearance

Monday, June 08, 2009

Today I had an ultrasound scan on my leg which confirmed the presence of a DVT in my lower thigh. This means three months of low molecular weight heparin by injection every day. I am awake at last on day 7 of this course. Let's hope for good news after my CT scan

Saturday, June 06, 2009

The past couple of days have been the worst so far. The peripheral neuropathy has been more severe and I have spent most of the time asleep, unable to rouse myself for anything. I also seem to have developed a deep venous thrombosis, with calf pain. They have started me on clexane.

I really don't think I could take another course of chemotherapy at this dose.

The first five verses of John chapter 17 gives us a close contact with the Lord Jesus Christ, for they tell us what he prays for himself. They also illuminate the meanings of “Christian” words or phrases that may astonish us.

The first word is “authority” (v2). This is a word much devalued by recent events. We complain about an authoritarian government. We look at British MPs and jeer at their assumed authority. Our leaders in almost every profession have become figures of fun. George Bush became a laughing stock, military leaders were undone by the scandals in Iraqi prisons, scientists are derided as they will say anything in order to get research grants, bankers have misled us and trousered huge bonuses in payment for failure, industrial giants have collapsed, the Roman Catholic church is mired by allegations of child abuse, doctors have been besmirched by the activities of Harold Shipman and others. Islamic leaders are seen as terrorists and murderers. Teachers are unable to control classrooms, the police are corrupt or racists and the list goes on.

A recent poll in Britain concluded that the majority of respondents thought that politicians were in it to feather their own nests rather than serve their constituents. For some reason they would rather be governed by celebrities, actors or pop-singers. Authority is seen to be something to be avoided, though the reputation of those who seek “freedom” for authority was hardly enhanced by the arrest of the man alleged to be the murderer of the abortion doctor last week.

Jesus gives a new meaning to authority. Authority was given to Jesus so that he might give eternal life to those that were given him.

Authority is about giving not taking. Even the best governments take from us in the form of taxes. Here is an authority that is about giving.

The second phrase is “eternal life”. “Pie in the sky when you die” say the sceptics. And we have to admit that we think of eternal life as something that begins when we die, but Jesus defines it differently. “This is eternal life: that they may know you, the only true God, and Jesus Christ, whom you have sent.” (v3) Eternal life is about relationships. The word “know” implies the most intimate relationship possible. Jesus came that we might know God intensively. Forever. Beginning now. God the Holy Spirit indwells every believer. How many of us make ourselves aware of his presence. I don’t mean in a theatrical way, waving our arms about, speaking in a language that no-one understands, but being conscious that ever word you say and every action you take is observed by him, that every thought you have is available to him, and that if you learn to listen to him he will prompt your thoughts and actions according to God’s will. Take time to be silent and listen to him and get your mind right by reading his word regularly. You can be sure that it is his words you are listening to by checking against what he has already said.

The third word is “glory”. Again glory is something that means less today than once it did. Newspaper headlines ascribe glory to football teams, dancers on TV, and Oscar winners. Once it attended empires, now a pub cricket team has it for winning a 20-over knockabout. How glory has been devalued. Yet it was once an attribute of magnificence, demanding awe and worship. Fanfares and parades, processions with elephants strung with jewels and gold, soldiers and slaves, dancing girls and jugglers, drums and trumpets; Hollywood had it down to a ‘T’.

Yet Jesus had it differently: “I have brought you glory on earth by completing the work you gave me to do. And now, Father, glorify me in your presence with the glory I had with you before the world began.” (vv 4-5).

What was the work that Jesus had come to do? Why, to redeem sinners. But this task had not been completed when the prayer was prayed. Nevertheless, Jesus was resolute that it would be so. He had set his face towards the cross and would not be diverted even when passionately considering all the options in Gethsemane. The task given was to bring all those who were given to him to eternal life (v2); this would be done and this was the key to glory. We talk about the glory of the cross, but if the cross was all their was, it would not be glory. The Resurrection is the affirmation that the cross was effective and Pentecost is the demonstration of its effectiveness.

Glorious though the cross was, I sometimes think we get stuck there. Surely we should preach Jesus Christ and him crucified, but that is the key to an eternal life of knowing God, not an end in itself. We should never forget the debt we owe, but we should not forget to ‘pick up our winnings’. Some Christians seem to want to leave them on the table and play the game over and over again. Our sins have been wiped away. Not only forgiven but forgotten. If we brought them up at the Judgement Seat they would be answered with, “When was that then, we have no record of that here?” Of course we have to keep short records with God and be ready to confess the sins of the day in the sure knowledge that “If we confess our sins, He is faithful and just to forgive us our sins and to cleanse us from all unrighteousness.”

The chief end of Man is to love God and enjoy Him forever. It’s the ‘enjoy him forever’ that we are missing out on. Miserable Christians everywhere, start smiling. Laugh! Enjoy yourself!

CS Lewis was a student of medieval and renaissance literature. Their model of the Universe was one guided by the planets, with seven spheres of influence. A recent book by Michael Ward “Planet Narnia” describes how each of the Narnia books is concerned with the atmosphere engendered by each of the seven planets (not our planets, but theirs – the sun, the moon, Mercury, Venus, Mars, Jupiter and Saturn.) The first in the series “The lion, the witch and the wardrobe” is assigned to Jupiter (or Jove) and Aslan is a Jovial character, kingly yet full of joy and mirth.

I have always enjoyed the poetry of John Donne and the War Poets, Wilfred Owen and Siegfried Sassoon. Lewis calls them writers about death under Saturnine influence. To quote Narnia, “It’s always winter and never Christmas.” Lewis was also a subaltern at the Western Front. He saw equally terrible things, but after a period of grief he saw it as time to move on. Poets have seldom been good at glory in the way that musicians or architects and painters have. Francis Schaeffer was convinced that we should enjoy these glorifications of Christ as their makers intended. He was no iconoclast. Puritans and Hypercalvinists have despised such attempts as idolatry, and of course they can be used as such, but as aids to worship I see no sin. Certainly, I could stand never singing “Shine Jesus Shine” again for the chance of standing in the nave of Salisbury Cathedral or forfeit another chorus of Celebration for the chance of taking part in Handel’s Messiah at Huddersfield Town Hall. The are joys to be had in the Christian life and we must not despise them.

Monday, June 01, 2009

Sorry to have been silent for so long. Two things: the side effects lasted longer this time than usual; that in itself would not have stopped me blogging, but I have also swapped my computer system. That has meant that I did not have enough 'oomph' to set it up with an internet connection. Today, feeling better, and with the help of my son, I have been able to set up a wi-fi connexion.

Anyway I have been able to do some work on the CLL chapter that I have to produce. Here is the introduction:

Most people begin their article on chronic lymphocytic leukemia (CLL) with the words “CLL is the commonest leukemia in the Western world”. It may or not be true, but with recent changes in the definition of the disease we can no longer be sure. Not only that, but the general impression that CLL is getting commoner and more benign may simply be an accident of disease discovery, with more alert physicians recognizing a disease that may or may not be there.

A new heterogeneity in CLL was discovered a decade ago and this has provided a key to opening up the complex pathophysiology of the condition and coincidentally has important prognostic value. In addition, a range of new treatments has become available during this time as well as the means of detecting minimal residual disease. As a result we now have to look at CLL differently. For some patients this will mean that we may never treat their leukaemia, but may still have to manage late complications; for others we will hold out the prospect of cure, though this will not be without hazard; for yet others there will be a sequence of treatments and remissions with the physician balancing benefit and harm with the aim of producing the longest possible, good quality life.

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About Me

Born in Worcester, England 1943; school at Farnborough, Hampshire 1954-62; University 1962-7 and junior doctor posts 1967-74 in Bristol; Consultant Haematologist Bournemouth 1974-2003; Professor of Immunohaematology Southampton 1986 to present. Honorary Consultant Haematologist Kings College Hospital, London, 2004-present. After 5 years of working part time researching, writing, reviewing, editing, speaking, sitting on committees, advising, answering questions and thinking, I now think of myself as fully retired apart from my role as Editor in Chief of the medical journal Leukemia Research. I was awarded the Binet-Rai medal for outstanding research in CLL in 2002 and this has been my most sucessful area of research, but I have also made important contributions in the fields of apheresis, stem cell transplantation, myeloma, myelodysplastic syndrome, antibody therapy, cytokine therapy and DNA vaccines. I was once mascot for Aldershot Town Football. Club. Married to Diane for 44 years. Four children, Karen, Richard, Angela and David.